̽��ֱ�� of Cambridge - Alison Dunning

̽��ֱ�� academics ranked among best in the world

hcf38 — Thu, 21 Dec 2023 10:57:57 +0000

̽��ֱ��Research.com Best Female Scientists in the World 2023 rankings are based on an analysis of more than 166,000 profiles of scientists across the globe. Position in the ranking is according to a scientist’s total ‘H-index’ - rate of the publications made within a given area of research as well as awards and recognitions. Only the top 1000 scholars with the highest H-index are featured in the ranking.

Kay-Tee Khaw, an Emeritus Professor in Gerontology and a Gonville & Caius Fellow, is placed fifth worldwide and tops the list for Europe. Professor Khaw, who was named a CBE in 2003 for Services to Medicine, published a study on how modest differences in lifestyle are associated with better life expectancy which informed the UK Government’s ‘Small changes, big difference’ campaign in 2006.

Also high in the rankings is Barbara Sahakian, Professor of Clinical Neuropsychology in the Department of Psychiatry and a Fellow of Clare Hall, who is placed sixth in the UK. Professor Sahakian’s recent research includes a study showing the benefits to mental health and cognitive performance of reading for pleasure at an early age, and seven healthy lifestyle factors that reduce the risk of depression.

Joining Professor Khaw and Professor Sahakian in the top 10 in the UK is Carol Brayne, Professor of Public Health Medicine in the Department of Psychiatry and Fellow of Darwin. Awarded a CBE in 2017 for Services to Public Health Medicine, Professor Brayne has pioneered the study of dementia in populations.

Nine other ̽��ֱ�� of Cambridge scientists also make the rankings:

Professor Gillian Murphy (Department of Oncology), an international leader in the field of metalloproteinases, who has defined their roles in arthritis and cancer.

Professor Claudia Langenberg (MRC Epidemiology Unit), a public health specialist combining her expertise with research focused on molecular epidemiology.

Professor Nita Forouhi (MRC Epidemiology Unit), a physician scientist, MRC Investigator and Programme Leader in Nutritional Epidemiology, whose research on the link between diet, nutrition and chronic diseases like type 2 diabetes has informed health policy.

Professor Alison Dunning (Centre for Cancer Genetic Epidemiology, Department of Oncology), a genetic epidemiologist working on the risk of breast and other hormonal cancers.

Professor Karalyn Patterson (MRC Cognition and Brain Sciences Unit, Cambridge Centre for Frontotemporal Dementia and Related Disorders), a Fellow of Darwin College, who specialises in what we can learn about the organisation and neural representation of language and memory from the study of neurological patients suffering from the onset of brain disease or damage in adulthood.

Professor Dame Clare Grey (Department of Chemistry), a materials chemist whose work has paved the way for less expensive, longer-lasting batteries and helped improve storage systems for renewable energy, she is Chief Scientist and co-founder of Nyobolt, a company that is developing ultrafast-charging batteries for electric vehicles.

Professor Sharon Peacock (Department of Medicine), who has built her scientific expertise around pathogen genomics, antimicrobial resistance, and a range of tropical diseases, was the founding director of the COVID-19 Genomics UK Consortium which informed the COVID-19 pandemic response.

Professor Maria Grazia Spillantini (Department of Clinical Neurosciences and Fellow of Clare Hall) has been researching the cause of dementia for many years and was the first to identify the specific protein deposit found in Parkinson’s disease.

Professor Dame Theresa Marteau (Department of Public Health and Primary Care and Honorary Fellow of Christ’s College), a behavioural scientist, focuses on the development and evaluation of interventions to change behaviour (principally food, tobacco and alcohol consumption) to improve population health and reduce health inequalities, with a particular focus on targeting non-conscious processes.

Speaking on publication of this year’s rankings, Imed Bouchrika, Co-Founder of Research.com and Chief Data Scientist, said: “ ̽��ֱ��purpose of this online ranking of the world's leading female scientists is to recognize the efforts of every female scientist who has made the courageous decision to pursue opportunities despite barriers.

“Their unwavering determination in the face of difficulties serves as a source of motivation for all young women and girls who pursue careers in science.”

Twelve academics from the ̽��ֱ�� of Cambridge have been ranked among the top female scientists in the world - with one claiming the top spot for Europe.

Gonville & Caius College

Professor Kay-Tee Khaw who has been named as the top female scientist in Europe by Research.com

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Detailed genetic study provides most comprehensive map of risk to date of breast cancer risk

cjb250 — Tue, 07 Jan 2020 16:00:31 +0000

̽��ֱ��results, published today in the journal Nature Genetics, provide the most comprehensive map of breast cancer risk variants to date. ̽��ֱ��researchers involved, from over 450 departments and institutions worldwide, say the findings will help provide the most detailed picture yet of how differences in our DNA put some women at greater risk than others of developing the disease.

̽��ֱ��majority of the DNA is identical between individuals, but there are some differences, known as genetic variants, and these changes can have a profound effect, increasing an individual’s susceptibility to disease.

Our DNA – the blueprint for the human body – contains between 20,000-25,000 genes. Many of these code for proteins, the building blocks that make up the human body. Genetic variants can be located within genes, altering the protein. However, most of genetic variants are located outside genes, sometimes regulating the function of genes, turning their ‘volume’ up or down or even off. Finding which gene is targeted by these variants is not straightforward.

Most diseases are complex, polygenetic diseases – in other words, no single genetic variant or gene causes the disease, but rather the combination of a number of them act together to increase the likelihood that an individual will develop a particular disease. Breast cancer is one such disease.

Previous genome-wide association studies (GWAS), which involve comparing the DNA of patients against that of healthy controls, have found around 150 regions of the genome that clearly affect breast cancer risk. Within these regions, researchers know there are one or more genetic changes that affect the risk of developing cancer, but rarely are they able to pinpoint the specific variants or genes involved. Fine-mapping studies, such as this one, allow scientists to narrow down which variants contributing to the disease, how they might work and predict which are the genes involved.

“We know from previous studies that variants across our DNA contribute towards breast cancer risk, but only rarely have scientists have been able to identify exactly which genes are involved,” said Dr Laura Fachal from the Wellcome Sanger Institute. “We need this information as it gives us a better clue to what is driving the disease and hence how we might treat or even prevent it.”

In this new study, researchers from hundreds of institutions worldwide collaborated to compare the DNA of 110,000 breast cancer patients against that of some 90,000 healthy controls. By looking in much closer detail than was previously possibly, they identified 352 risk variants. It is not yet clear exactly how many genes these target, but the researchers have identified 191 genes with reasonable confidence; less than one in five of these had been previously recognised.

“This incredible haul of newly-discovered breast cancer genes provides us with many more genes to work on, most of which have not been studied before,” said Dr Alison Dunning from the ̽��ֱ�� of Cambridge. “It will help us build up a much more detailed picture of how breast cancer arises and develops. But the sheer number of genes now known to play a role emphasises how complex the disease is.”

Of the newly-discovered genetic variants, a third predispose women towards developing hormone-responsive breast cancer, the type of disease found in four out of five breast cancer patients, which respond to hormonal treatments such as tamoxifen. 15% of the genetic variants predispose women to the rarer type, estrogen-receptor-negative breast cancer. ̽��ֱ��remaining genetic variants play a role in both types of breast cancer.

In the majority of cases, the genetic change affected gene expression – in other words, how active a particular gene was and how much of a particular protein it created – rather than altering the type of protein itself. For instance, nine different variants regulate the same gene, the Estrogen Receptor (ESR1) gene. Many other variants affect places in the DNA where the Estrogen Receptor protein binds, and, in turn regulates other genes. This highlights the importance of the ESR1 gene and its protein product, the Estrogen Receptor, in breast cancer development.

While each genetic variant only increases the risk of developing breast cancer by a very small amount, the researchers say that added together, these will allow them to ‘fine tune’ genetic testing and give women a much clearer picture of their genetic risk. This will then allow doctors and clinicians to provide advice on the best strategy for reducing their risk and preventing onset of the disease.

Professor Doug Easton, also from the ̽��ֱ�� of Cambridge, said: “Our work would not have been possible without the help of the 200,000 volunteers who allowed us to study their DNA. It is also testament to the work of hundreds of researchers from all over the world who collaborated on this study.”

Reference
Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature Genetics; 7 Jan 2020; DOI: 10.1038/s41588-019-0537-1

A major international study of the genetics of breast cancer has identified more than 350 DNA ‘errors’ that increase an individual’s risk of developing the disease. ̽��ֱ��scientists involved say these errors may influence as many as 190 genes.

̽��ֱ��sheer number of genes now known to play a role emphasises how complex the disease is

Alison Dunning

qimono

DNA

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Breast cancer genetic variants found to alter how cells respond to oestrogen

cjb250 — Mon, 29 Feb 2016 16:52:02 +0000

Breast cancer is the most common type of cancer among women. Around one in eight women in the general population is expected to develop the disease at some point in her life. ̽��ֱ��majority of cases occur in women aged 50 and over.

̽��ֱ��female sex hormone oestrogen acts as a trigger, binding to a molecule known as an oestrogen receptor in most breast cells and triggering a cascade of signals that cause the cell to behave normally. However, the oestrogen receptor is switched off in some cells and these do not respond to the hormone.

An international collaboration, led by researchers at the ̽��ֱ�� of Cambridge and the QIMR Berghofer Medical Research Institute, examined the DNA surrounding the gene for the oestrogen receptor – known as ESR1 – in women with different types of breast cancer against those of healthy controls to identify genetic variants responsible for an increased risk of breast cancer. ̽��ֱ��results are published today in the journal Nature Genetics.

Among their findings, the researchers discovered five cancer-risk variants based within or around the ESR1 gene. This gene has long been known to be related to the risk and progress of breast cancer, but little is understood of how it works and why it should affect breast cancer.

Of the five variants discovered by the team, four were more strongly associated with tumours where the ESR1 gene is switched off, so the tumour cells have no oestrogen receptors. These represent around one fifth of breast cancers.

One of these four variants was of particular interest as it was associated with a rarer type of breast tumour that contain active receptors for the protein known as ‘human epidermal growth factor 2’ (HER2). Such tumours can be treated by the drug trastuzumab (marketed as Herceptin). This is believed to be the first time a specific genetic risk factor for HER2 positive breast tumours has been found.

Dr Stacey Edwards’ team from QIMR Berghofer, Brisbane, had been searching for gene regulatory elements around the ESR1 gene, which act like the volume controls on a radio or TV, turning the activity of the nearby genes up or down. There are two major types of gene regulators: ‘enhancers’, which increase activity of the genes express such that they make more protein, and ‘silencers’, which have the opposite effect.

When the Cambridge and Brisbane teams compared notes, they spotted that four of the breast cancer risk variants coincided with ‘volume-up’ enhancers. These particular regulators did not just affect the ESR1 gene but also other nearby genes. ̽��ֱ��variants that increased risk of breast cancer directly reduced the effectiveness of each enhancer, hence turning down the volume of ESR1 and the other nearby genes. This reduced the amount of oestrogen receptor produced by breast cells.

̽��ֱ��researchers say that their results suggest the ESR1 gene works with other nearby genes to affect breast cancer development.

̽��ֱ��fifth genetic variant was found to be more strongly associated with tumours where the oestrogen receptor is switched on. This variant coincides with and alters the effectiveness of ‘volume-down’ silencer, which means that it increases the amount of oestrogen receptor protein produced by breast cells.

“It’s interesting that all five of the genetic variants that we have found affect levels of oestrogen receptors in breast cells,” says Dr Alison Dunning from the Department of Oncology at the ̽��ֱ�� of Cambridge, one of the lead authors on the study. “This suggests that there may be a ‘Goldilocks’ level of these receptors in breast cells: too few or too many and the breast cells are more likely to become cancerous.”

“As our research looks at how tumours with and without the oestrogen receptor are regulated, it’s possible it could help make sense of the enduring mystery of how tamoxifen works and why tumours develop in these two divergent ways,” says Dr Edwards, one of the study’s senior authors. “Our findings could open the way to developing new, more specific breast cancer preventions.”

̽��ֱ��genetic variants are all very common, each one carried by around one in three women. Each variant only increases the risk of developing breast cancer by a small amount.

Professor Doug Easton, another senior author from the ̽��ֱ�� of Cambridge, adds: “breast cancer is a very complex disease, with many genes, and other factors, contributing to an overall increased risk of developing the disease. These five common variants that we have identified will contribute to an eventual predictive test for breast cancer risk, and for determining the risk of the particular subtype of breast cancer, that will include hundreds of similar variants.”

Funding for the study came from organisations including the European Union, Cancer Research UK, the National Health and Medical Research Council of Australia and the Australian National Breast Cancer Foundation.

Dr Alan Worsley, Cancer Research UK’s senior science information officer, said: “We know that hundreds of genes are likely to play a role in how cancers start. And this latest study adds more detail to our genetic map of breast cancer risk, potentially helping understand which type of breast cancer is likely to develop based on a woman’s genetic makeup. Understanding more about each individual’s risk of cancer could help us find ways to potentially prevent the disease or pick it up in its earliest stages."

Reference
Dunning, AM et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1. RMND1 and CCDC170. Nature Genetics; published online 29 Feb 2016. DOI: 10.1038/ng.3521.

An international study of almost 120,000 women has newly identified five genetic variants affecting risk of breast cancer, all of which are believed to influence how breast cells respond to the female sex hormone oestrogen.

There may be a ‘Goldilocks’ level of oestrogen receptors in breast cells: too few or too many and the breast cells are more likely to become cancerous

Alison Dunning

williami5

Breast cancer reflection

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Cancer: what's on the cards?

bjb42 — Mon, 04 Jan 2010 14:28:37 +0000

How likely we are to develop cancer is determined by our genes and our lifestyle. Likening this to a hand of cards, the risk of cancer depends on whether we inherit good cards or bad cards and also how we play them (our lifestyle). Some genes carry a very high risk, which is why some individuals have a particularly strong family history of cancer. Most of the time, however, cancer risk is determined by a combination of genes conferring a more moderate risk; nevertheless, the overall risk can be high (a bad hand) if there are enough of these genes.

At Strangeways Research Laboratory (SRL) in Cambridge, the research groups of Professor Doug Easton, Dr Paul Pharoah and Dr Alison Dunning, supported with over £9 million of funding from Cancer Research UK, are working out the role of normal human genetic variation in cancer risk – essentially, which hands of cards are worse than others.

̽��ֱ��SEARCH begins

Several high-risk gene defects, such as mutations in BRCA1 and BRCA2 in breast cancer, have been identified through family studies. Work in the 1990s at SRL by Professor Sir Bruce Ponder, who is now Director of the Cancer Research UK Cambridge Research Institute (CRI), and Professor Easton helped track down these two genes. However, among the general population, these defects are usually rare, and most cancers are the result of inheriting several more-common gene mutations. For breast cancer, these more-common gene defects account for as much as 80% of inherited risk, according to findings at SRL.

‘ ̽��ֱ��trouble is, the individual effects of common genetic variants are small and to get reliable evidence about specific variants you need to sample large numbers of people,’ explained Professor Easton, Director of the Cancer Research UK Genetic Epidemiology Group. Key to finding these mutations has been the assembly at SRL of one of the largest population studies of cancer ever conducted, along with the unique expertise that the team has gathered together in cancer epidemiology, biostatistics, large-scale genetic analysis and public health medicine.

This work was started in 1996 by Professor Ponder and Professor Nicholas Day, who recruited Dr Paul Pharoah as a Clinical Fellow to enrol patients with breast cancer. ̽��ֱ��enrolment was later extended to include patients with ovarian, colorectal or uterine cancer, as well as participants with no history of cancer. ̽��ֱ��project, now called SEARCH, was further extended five years ago to include bladder, brain, kidney, oesophageal and pancreatic cancers, as well as melanoma and non-Hodgkin’s lymphoma. ‘Our early investment in well-curated and very large study sets, with blood samples, pathology review and clinical data, has been absolutely crucial as it has provided the statistical power for reliable conclusions about common genetic variants,’ explained Professor Ponder. Today, SEARCH numbers nearly 27,000 cases and normal controls from the East Anglia region, providing a remarkable and growing resource: by 2013, the hope is that this will have expanded to 35,000.

Going global

‘SEARCH has shown that the size of the dataset is really important for assessing the impact of common genetic variants accurately,’ explained Dr Pharoah, who leads a research group at SRL from the Department of Oncology. ‘ ̽��ֱ��logical next step was to combine data from SEARCH with other studies that had been happening worldwide.’

Cambridge now coordinates five international consortia of study groups: two consortia studying breast cancer, one each studying ovarian and prostate cancers, and a newly formed consortium to examine genetic differences underlying adverse side-effects from cancer radiotherapy (see below). From SRL, the consortia pull in not just SEARCH but also other studies such as ProtecT, a prostate cancer study led by Cambridge’s Professor of Surgical Oncology, David Neal, together with Professor Freddie Hamdy in Oxford and Professor Jenny Donovan in Bristol; and the familial breast cancer study EMBRACE, led by Professor Easton. ̽��ֱ��scale of the endeavour is unprecedented in population studies, and the European Union has recently awarded €12 million to coordinate these large-scale genetic studies in breast, ovarian and prostate cancers.

‘Apart from increasing the reliability of the data,’ said Professor Easton, ‘the international consortia afford the opportunity to study populations from different parts of the world where different genetic and lifestyle factors are operating.’

Gene hunting

Improvements in technology that would have been hard to imagine when SEARCH began are now being used to analyse the data, demonstrating the enormous foresight in setting up such a resource a decade ago.

‘We know that there are about 10 million variants in the genome, but choosing the right ones to test for association with cancer has in the past owed a great deal to chance, with the result that very few positive associations were identified,’ said Dr Dunning, who leads the high-throughput laboratory team within the SRL. ‘Now, though, thanks both to the ability to carry out genome-wide scans and the samples collected through the international consortia, we can pinpoint the variants that are definitively linked to the risk of cancer.’

A full genome scan for breast cancer, the first of its kind, was completed in 2007 by the researchers and published in Nature. Full genome scans of prostate and ovarian cancers have since followed in Nature Genetics. In the latest scan, published in October 2009, the genomes of 38,000 men with and without prostate cancer were analysed for over 43,000 single differences in DNA (called single nucleotide polymorphisms or SNPs), revealing multiple new cancer gene regions.

To date, 13 predisposing gene regions have been identified for breast cancer, five for ovarian cancer and 27 for prostate cancer, findings that have significant implications for targeted screening and prevention in the future. Since most of these newly discovered regions contain genes that had not previously been considered in cancer, they will also provide new insights into the biology of the disease. Going forward, Professor Ponder’s group at the CRI is developing phenotypic assays as a read-out of cancer risk, studying how risk genes exert their function and searching for molecular markers for future studies of early diagnosis and prevention. Professor Fiona Watt at the Wellcome Trust Centre for Stem Cell Research is also studying the biological effects caused by these gene defects to understand what goes wrong in cancer.

Professor Neal, in the Department of Oncology and CRI, has been investigating whether a protein made by one of the newly discovered prostate loci can be used as a screening and diagnostic marker in prostate cancer since it can be measured in serum and urine. Early results suggest not only loss of the protein in prostate cancer, but also a decrease in men who possess the high- risk form of the gene but who have not yet developed prostate cancer.

Translational tools

But what does this all mean to understanding our own risk? For breast and ovarian cancer, Dr Antonis Antoniou and Professor Easton have developed a computer model named BOADICEA that can predict an individual’s risk of these cancers. ̽��ֱ��tool is already being used by genetic counsellors to identify high-risk individuals, referring them for counselling and regular screening if appropriate, and providing advice about ways to lower their risk. As new data come to light from the genome scans, BOADICEA will continually be improved, providing increasingly accurate information to individuals wishing to know the hand of genetic cards that they’ve been dealt.

BCAC: Breast Cancer Association Consortium

BOADICEA: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm

CIMBA: Consortium of Investigators of Modifiers of BRCA1/2

EMBRACE: Epidemiological Study of Familial Breast Cancer

OCAC: Ovarian Cancer Association Consortium

PRACTICAL: Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome

ProtecT: Prostate Testing for Cancer and Treatment

SEARCH: Studies of Epidemiology and Risk Factors in Cancer Heredity

For more information, please contact Professor Doug Easton (doug.easton@srl.cam.ac.uk), Dr Paul Pharoah (paul.pharoah@srl.cam.ac.uk) and Dr Alison Dunning (alisond@srl.cam.ac.uk) at the Strangeways Research Laboratory or visit the SEARCH website.

Scientists at Strangeways Research Laboratory are leading the search for the ‘genetic cards’ that determine an individual’s risk of cancer.

Ben Alford on Flickr

Cards

Worldwide consortia led by Strangeways Research Laboratory

BCAC: 100,000 breast cancer cases and controls; 55 study groups

CIMBA: 25,000 breast cancer cases and controls; 42 study groups

OCAC: 30,000 ovarian cancer cases and controls; 34 study groups

PRACTICAL: 25,000 prostate cancer cases and controls; 27 study groups

Radiogenomics Consortium: newly formed; 23 study groups

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